Treatment strategies for hepatocellular carcinoma with extrahepatic metastasis

Table 1 Data from phase III trials for first-line and second-line therapy of hepatocellular carcinoma

	Drugs	Level of evidence	Absolute OS (mo)	Comparison between OS	ORR	ClinicalTrials.gov Number
First-line setting
SHARP[7] (n = 602)	Sorafenib vs placebo	Phase III	10.7 vs 7.9	HR 0.69 (95%CI: 0.55-0.78)	RECIST, 2% vs 1%	NCT00105443
Asia-Pacific[8] (n = 271)	Sorafenib vs placebo	Phase III	6.5 vs 4.2	HR 0.68 (95%CI: 0.50-0.93)	RECIST, 3.3% vs 1.3%	NCT00492752
REFLECT[9] (n = 954)	Lenvatinib vs Sorafenib	Phase III	13.6 vs 12.3	HR 0.92 (95%CI: 0.79-1.06)	mRECIST, 24.1% vs 9.2%	NCT01761266
IMbrave150[36] (n = 501)	Atezolizumab + Bevacizumab vs Sorafenib	Phase III	NE vs 13.2	HR 0.58 (95%CI: 0.42-0.79)	RECIST 1.1, 27% vs 12%; mRECIST, 33.2% vs 13.3%	NCT03434379
Second-line setting
RESORCE[10] (n = 573)	Regorafenib vs placebo	Phase III	10.6 vs 7.8	HR 0.63 (95%CI: 0.50-0.79)	mRECIST, 10.6% vs 4.1%	NCT01774344
CESETIAL[11] (n = 707)	Cabozantinib vs placebo	Phase III	10.2 vs 8.0	HR 0.76 (95%CI: 0.63-0.92)	RECIST 1.1, 4% vs 0.4%	NCT01908426
REACH-2[13] (n = 292)	Ramucirumab vs placebo	Phase III	8.5 vs 7.3	HR 0.71 (95%CI: 0.53-0.95)	RECIST 1.1, 4.6% vs 1.1%	NCT02435433
CheckMate 459[39] (n = 743)	Nivolumab vs Sorafenib	Phase III	16.4 vs 14.7	HR 0.85 (95%CI: 0.72-1.02)	RECIST, 15% vs 7%	NCT02576509
KEYNOTE-240[41] (n = 413)	Pembrolizumab vs placebo	Phase III	13.9 vs 13.6 vs 10.9	HR 0.78, 95% CI: 0.61-0.99)	RECIST 1.1, 18.3% vs 4.4%	NCT02702401

OS: Overall survival; ORR: Objective response rate; HR: Hazard ratio; 95%CI: 95% Confidence interval; RECIST: Response evaluation criteria in solid tumors; mRECIST: Modified RECIST for hepatocellular carcinoma; NE: Could not be evaluated.